This protocol will investigate the antidepressant venlafaxine as a potential pharmacotherapy for cocaine abuse. Both tricyclic and selective serotonergic reuptake inhibitor therapies for cocaine abusers have been attempted, with few successes. Tricyclic therapy for cocaine abusers was based on the hypothesis that the anhedonia and anergia observed after chronic cocaine use is due to cocaine-engendered postsynaptic dopaminergic receptor supersensitivity and that TCA's could reverse that effect. Although initial reports with both open- and double-blind trials were positive, other trials with these medications have not been as promising. Because cocaine's inhibition of serotonin uptake is two to four times greater than its inhibition of dopamine uptake, serotonergic regulation may be an effective target for cocaine pharmacotherapy. However, despite initial promising results with fluoxetine in an open trial of methadone-maintained cocaine dependent patients, in our laboratory, fluoxetine maintenance affected neither cocaine craving nor choice of cocaine. To date, the data do not suggest that future studies focusing on medications which primarily regulate central serotonin will be fruitful. It seems likely, given the results of clinical trials, that an effective medication to treat cocaine abusers will have to be novel in action and have multiple mechanisms of action. We propose to study the newer antidepressant, venlafaxine, a phenylethylamine which blocks both the norepinephrine and serotonin transporter complexes with nearly equal affinity but has 10-fold lower affinity for the dopamine transporter. Our choice of venlafaxine is based largely on the dramatic results we have found in our NIDA Center-supported Cocaine Treatment Clinic. In the first ten patients enrolled, all of whom had cocaine dependence and desipramine-refractory major depression, two achieved total abstinence, and seven had greater than 75% reduction in cocaine use by self-report and urine toxicology at 12 weeks. As this was a depressed sample, the generalizability of these data to the broader cocaine-dependent population is uncertain. However, venlafaxine appears sufficiently promising to test in our laboratory, and therefore we plan to study it.